Metabolic syndrome is an energy storage disorder characterized by abdominal obesity, high blood sugar, hypertriglyceridemia, low HDL, hypertension, and fatty liver disease (steatosis). It has been established that nearly one quarter of all Americans have metabolic syndrome and that the major cause of mortality in these patients is athero-thrombotic disease. As rates of metabolic syndrome increase with age, this syndrome represents a massive challenge to public health and major financial strain on society. The liver plays a critical role in controlling metabolism and production of pro-thrombotic factors which underlie the development and progression of atherosclerosis. Notably, patients with fatty liver disease and steatohepatitis often develop into a hyper-coagulable state. One potential mechanism that may unite the metabolic syndrome-atherosclerosis axis is activation of the G-protein coupled receptor Protease-Activated Receptor-2 (PAR2) by the coagulation factors VIIa, Xa, and tissue factor (TF). Emerging evidence points to a role for PAR2 in lipid metabolism in addition to the development of metabolic syndrome and atherosclerosis. We have recently identified a novel and potentially therapeutically relevant compound called PZ-2 5, a pepducin, which inhibits PAR2. Pepducins are short polypeptides attached to a fat molecule allowing the pepducin to freely diffuse through a cell membrane and inhibit the inner face of the target receptor. PAR2 inhibition or genetic deficiency appears to inhibit the onset of diet induced obesity and steatosis, additionally numerous studies have shown that PAR2 has an important role in the development of atherosclerosis. The first aim of this study will be to evaluate if PZ- 5 treatment or PAR2 genetic deficiency can reduce: steatosis, systemic levels of factors VIIa and Xa, and monocyte activation in mice fed a high-fat and high-sugar (HFS) diet. The prediction is that the lack of PAR2 signaling will reduce hypertriglyceridemia as well as monocyte activation and foam cell development. The second aim of this study will identify the contributions of metabolic dysfunction and altered lipid profiles to the development of foam cells by comparing mice fed a HFS or high-cholesterol diet. The expectation is that reductions in steatosis, caused by the HFS diet, brought on by PAR2-blockade or deficiency will reduce the total number of lipid particles and foam cell development. Relevance to human health: The research proposed in this fellowship will define the mechanisms by which metabolic syndrome causes the development of cardiovascular disease and describe ways of addressing these mechanisms in a therapeutically relevant manner. Successful completion of the proposed studies will broaden our understanding of the role of metabolism in the development of cardiovascular disease and increase the options that are available for therapeutic intervention.